Protein kinase C (PKC) is a family of isozymes which plays a crucial role in signal transduction for a variety of biologically active substances which activate cellular functions and proliferation. The ability to selectively modulate the members of this family offers the opportunity for the development of tools for the investigation of many cellular processes as well as for the development of new pharmaceuticals for the treatment of diseases such as cancer, AIDS, cardiovascular diseases, and diseases, and diseases of the CNS and immune system. The proposed project will apply to the indolactam class, techniques and information which have been successfully applied by the applicant to the development of PKC isozyme-selective modulators in other classes of "phorboids". Thus, a series of carefully planned analogs and derivatives of indolactam V will be prepared by total synthesis and evaluated for isotype-selective binding using a broad panel of rDNA-derived PKC isozymes. The SAR information obtained during this study will be integrated into a model of the functioning of the regulatory sites of the PKC isozymes. Selective modulators from the initial screen will be further tested for agonist/antagonist properties in the PKC isozymes and in functional assays including: anti-cancer, anti-HIV and platelet functions.